Genesis Of Lung Cancer Research Articles

Lung cancer: “Epidemiology and risk factors”

Bronchopulmonary cancers are common cancers with a poor prognosis. It is the leading cause of death by cancer in Algeria and in the world. Behind this unfavorable prognosis hides numerous disparities according to age, sex, and exposure to risk factors, ranking 4th among incident cancers and developing countries including Algeria, all sexes combined. It ranks 2nd cancers in men and 3rd among women. Whatever the age observed, the incidence of this cancer is higher in men than in women, however the gap is narrowing to the detriment of the latter. The results of scientific research agree to relate trends in incidence and mortality rates to tobacco consumption, including passive smoking. Furthermore, other risk factors are mentioned such as exposure to asbestos in the workplace or to radon for the general population, or even genetic predisposition. However, the weight of these etiological and/or predisposing factors is in no way comparable to that of tobacco in the genesis of lung cancer and the resulting mortality. We provide a literature review in our article on the descriptive and analytical epidemiology of lung cancer.

Epidemiology, Etiology, and Prevention of Lung Cancer

Bronchopulmonary cancers are common cancers with a poor prognosis. It is the leading cause of death by cancer in Algeria and in the world. Behind this unfavorable prognosis hides numerous disparities according to age, sex, and exposure to risk factors, ranking 4th among incident cancers and developing countries including Algeria, all sexes combined. It ranks 2nd cancers in men and 3rd among women. Whatever the age observed, the incidence of this cancer is higher in men than in women, however the gap is narrowing to the detriment of the latter. The results of scientific research agree to relate trends in incidence and mortality rates to tobacco consumption, including passive smoking. Furthermore, other risk factors are mentioned such as exposure to asbestos in the workplace or to radon for the general population, or even genetic predisposition. However, the weight of these etiological and/or predisposing factors is in no way comparable to that of tobacco in the genesis of lung cancer and the resulting mortality. We provide a literature review in our article on the descriptive and analytical epidemiology of lung cancer.

Faktor–Faktor Yang Berhubungan dengan Perilaku Merokok di Dalam Rumah

Lung cancer ranks on the first as the cause of death, which is 12.6% (Globocan, 2018). The genesis of lung cancer in Indonesia is based on data from the Friendship Center General Hospital, 87% of lung cancer cases are caused by smoking behavior, both passive and active smokers. The number of smokers in Indonesia is still high, the number of passive smokers is 78.4% or 133.3 million adults exposed to cigarette smoke in their homes. Passive smokers can be attacked by various diseases such as lung cancer and respiratory diseases because cigarette smoke contains more than 4000 chemicals. In addition, if it is associated with maternal and child health, smoking can cause ARI disease that attacks the human respiratory tract with the number of infected children mostly in children. The research objective was to determine the correlate factors to the smoking behavior in the home at Pekon Sukadamai of Gunung Alip Sub-District in Tanggamus Regency. This type of research is a quantitative research with a cross sectional study design. The population in this research were all households with infants and toddlers in Sukadamai Village, amounting to 63 families. The sample in this research amounted to 63 respondents. Sampling in this research used a total sampling technique. The analysis used the chi square test. The results of the research showed that there was no correlation between knowledge (p value 0.90) and attitude (p value 0.07) with smoking behavior in the home at Pekon Sukadamai of Gunung Alip sub-district in Tanggamus Regency (p value = 0.000). Suggestions for the community are expected to be more diligent in adding insight by following the counseling provided by the public health center.

Role of Microbiota in Lung Cancer: Focus on Immune-Checkpoint Inhibition

Lung cancer (LC) represents a global threat, being the deadliest tumor worldwide. A new hope comes from the immune-checkpoint inhibitors (ICIs), a novel therapeutic approach which reactivates the immune system against the cancer cells. ICIs are antibodies targeting the immune checkpoints and triggering T cells to actively recognize and eliminate malignant cells. Despite their demonstrated efficacy within a portion of LC patients, ICIs show some limitations. One is the potential development of resistance to therapy and tumor recurrence over time. The second one consists in the potential manifestation of immune-related adverse events which can be severe or even fatal. The research is currently working at a fast pace to identify novel biomarkers to tackle LC patients who may truly benefit from ICI-based therapy. Among the proposed source of biomarkers, lung and gut microbiota are currently studied. In this review, all of the up-to-date knowledge concerning the relationship occurring between the airways/gastrointestinal microbiota and LC genesis, development, as well as response to ICIs is discussed in depth. The current preclinical and clinical evidence support two main considerations: (1) The microbiota might be a suitable source of novel diagnostic and prognostic LC biomarkers and (2) The microbiota modulation can be a powerful therapeutic strategy to improve the efficacy of ICIs in LC patients. Overall, the microbiota populating the lungs and the intestine represent a novel valuable weapon against LC.

P2.03-56 Polymorphism ICAM-1 and Beta-3 Integrin Are Associated with the Development of Non-Small Cell Lung Cancer and the Prognostic Role of ICAM-1

Lung cancer is widespread cancer in the worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. ICAM-1 and β3 integrin have been have been found to be associated with the angiogenesis, tumor growth and metastasis in various tumor types. Our primary aim in this study was to explore gene polymorphisms in ICAM-1 and β3 integrin molecular pathway in NSCLC patients and to clarify whether these values are effective on the etiopathogenesis and prognosis of the disease. Sixty-nine patients with operable (T1-4N0-1M0) NSCLC patients and 120 healthy individuals between January 2012 and June 2018 were included in the study. The tumor samples were taken after resected specimen. Blood samples of the patients were also collected before surgical resection. ICAM-1 and β3 integrin gene polymorphisms were determined by using PCR-RFLP techniques. Also serum ICAM levels were determined by ELISA method. The stages of the tumor were constructed according to 8th staging system. There was no statistically significant difference between patient with NSCLC and healthy control groups with regard to β3 Integrin Leu33Pro gene polymorphism(p=0.182). However, in patients with NSCLC, AG genotype frequency and G allele carriers of ICAM K469E variant were found to be higher than the control group and the difference was statistically significant (OR:2,710 95%CI:1,364-5,376; p=0.005). It has been determined that having a G allele increased approximately 2,95 fold the risk of disease and also carrying of AGTC combined genotype increased (OR:2,95 95%CI:1,366-6,373; p=0.049). When patients were evaluated according to tumor stage, serum levels of ICAM-1 gene in early tumor stage was found to be significantly higher than in advanced tumor stage (p=0,013). No significant difference was found between the range of histopathological subtypes and serum ICAM levels (p>0,05). Also, no statistically significant association was found between serum ICAM levels and angiolymphatic invasion (p=0.101, perineural invasion(p=0.054), lymph node metastasis (p=0.585). ICAM-1 as an intercellular adhesion molecule seems to play an important role in lung carcinogenesis and it might play a role in the invasiveness of the tumor. However, β-3 integrin was not found to be associated with lung cancer development. The role of ICAM-1 in the genesis of lung cancer as well as immune mechanism should be further investigated.

Expression of miR-9 and miR-200c, ZEB1, ZEB2 and E-cadherin in Non-Small Cell Lung Cancers in Iran.

MicroRNAs (miRNAs) exert a critical influence on physiological and pathological processes through post-transcriptional modification of their mRNA targets. They play important roles in tumorigenesis and are considered to be potential diagnostic and prognostic biomarkers with various cancers. MiR-200c and miR-9 are regulatory elements that can have dual impacts as oncogenes and/or tumor suppressor genes. MiR-200c regulates two transcription factors, ZEB1 and ZEB2, while miR-9 is a regulatory factor for the E-cadherin protein which has a critical function in cell-cell junctions and is inhibited by two transcription factors ZEB1 and ZEB2. In this study, expression levels of miR-200c and miR-9, ZEB-1, ZEB-2 and E-cadherin were assessed in 30 non-small cell lung cancers (NSCLCs) by real-time qPCR. MiR-9 was down-regulated significantly in tumor tissues compared to normal adjacent tissues, while there was no significant change in expression level of miR-200c. On the other hand, ZEB1 demonstrated significant increase and ZEB2a decrease at the mRNA level. These results indicate roles for miR-9 and ZEB1 in genesis of lung cancer, although clinico-pathological associations were not evident. Further studies are necessary to assess implications for treatment of lung cancer.

Menstrual and reproductive factors and lung cancer risk: A pooled analysis from the international lung cancer consortium.

Many clinical features of lung cancer are different in women and men. Sex steroid hormones exert effects in nonreproductive organs, such as the lungs. The association between menstrual and childbearing factors and the risk of lung cancer among women is still debated. We performed a pooled analysis of eight studies contributing to the International Lung Cancer Consortium (4,386 cases and 4,177 controls). Pooled associations between menstrual or reproductive factors and lung cancer were estimated using multivariable unconditional logistic regression. Subgroup analyses were done for menopause status, smoking habits and histology. We found no strong support for an association of age at menarche and at menopause with lung cancer, but peri/postmenopausal women were at higher risk compared to premenopausal (OR 1.47, 95% CI 1.11-1.93). Premenopausal women showed increased risks associated with parity (OR 1.74, 95% CI 1.03-2.93) and number of children (OR 2.88, 95% CI 1.21-6.93 for more than 3 children; p for trend 0.01) and decreased with breastfeeding (OR 0.54, 95% CI 0.30-0.98). In contrast, peri/postmenopausal subjects had ORs around unity for the same exposures. No major effect modification was exerted by smoking status or cancer histology. Menstrual and reproductive factors may play a role in the genesis of lung cancer, yet the mechanisms are unclear, and smoking remains the most important modifiable risk factor. More investigations in large well-designed studies are needed to confirm these findings and to clarify the underlying mechanisms of gender differences in lung cancer risk.

Akciğer kanseri ve epigenetik değişiklikler

Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA expression, have been reported to play a major role in the genesis of lung cancer. DNA methylation, histone modifications, and RNA expression are epigenetic markers in assesment of early detection, prognosis and evaluation of treatment of lung cancer. In this rewiev we summarize the common epigenetic changes associated with lung cancer to give some clarity to its etiology, and to provide an overview of the potential translational applications of these changes, including applications for early detection, diagnosis, prognostication, and therapeutics.

M2 polarized macrophages induced by CSE promote proliferation, migration, and invasion of alveolar basal epithelial cells

Cigarette smoking plays an important role in the genesis of lung cancer, and tumor-associated macrophages (TAMs) are believed to accelerate the process. We therefore sought to clarify the relationship between cigarette smoking, TAMs and tumorigenesis. We treated macrophages (THP-1) with cigarette smoke extract (CSE) and found that the mRNA levels of IL-6, IL-10, IL-12 and TNF-α decreased, while TGF-β mRNA levels increased. CSE significantly inhibited the phagocytic ability of macrophages, as assessed by flow cytometric analysis of FITC-dextran internalization. JAK2/STAT3 was significantly activated by CSE, as determined by Western blot analysis. When the scavenger receptor CD163, a specific marker of M2 macrophages, was analyzed by flow cytometry, its expression was significantly increased. After inducing M2 polarization of THP-1 cells, we co-cultured macrophages and alveolar basal epithelial cells (A549). The proliferation of A549 cells was detected by the MTT assay and cell cycle analysis, while their migration and invasion were detected by scratch wound assay and transwell assay. The results showed that the proliferation, migration and invasion of A549 cells were significantly promoted by M2 macrophages but were slightly inhibited by CSE. In conclusion, we demonstrated that macrophage M2 polarization induced by CSE promotes proliferation, migration, and invasion of alveolar basal epithelial cells.

JARID1B modulates lung cancer cell proliferation and invasion by regulating p53 expression.

Although three therapeutic modalities (surgical resection, chemotherapy, and radiotherapy) have been established, long-term survival for lung cancer patients is still generally poor. Until now, the mechanisms of lung cancer genesis remain elusive. The JARID1B is a histone demethylase that has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. In present study, we found that JARID1B was overexpressed in lung cancer cell lines and lung cancer tissues but not in normal lung tissues. The proliferation and invasive potential of lung cancer cells was significantly increased by ectopic expression of JARID1B. Contrarily, RNA interference targeting JARID1B in lung cancer cells significantly decreased the proliferation and invasive potential of cells. Moreover, we also found that the expression of p53 was modulated by JARID1B. Overexpressed JARID1B cell exhibited greatly decreased p53 expression, whereas silencing of JARID1B expression dramatically increased p53 expression at both the messenger RNA (mRNA) and protein levels. Inhibition of p53 by small interfering RNA (siRNA) reversed the shJARID1B-induced suppression of proliferation and invasion. Our results collectively suggested that JARID1B expressed in lung cancer played a role in lung cancer cells proliferation and invasion, which may be partly associated with the p53 expression.

Combined Germline Variations of Thrombophilic Genes Promote Genesis of Lung Cancer

A large variety of familiar and non-familiar lung carcinomas (LC) are caused by long term exposure to chemical carcinogens that are present in tobacco smoke. We aimed to investigate the prevalence of 5 thrombophilic germ-line mutations in patients with lung carcinomas. A total of 52 LC patients and 212 healthy controls from same population were analyzed for FV Leiden, factor V H1299R (R2), PAI-1, MTHFR C677T, MTHFR A1298C, ACE I/D, and Apo E genes and compared. Overall, heterozygous and/or homozygous point mutations in FV Leiden Apo E2, PAI-1 and MTHFR C677T genes were associated with LC in the current cohort. There was no meaningful association between LC and ACE I/D gene markers. The current results showed that LC is related to combined thrombophilic gene mutations and individuals with homozygosity of 4G in PAI-1 and MTHFR C677T genes and heterozygosity of FV Leiden, Apo E4 genes have a germ-line risk for LC tumorigenesis.

AB 43. The corticotropin releasing factor system in lung cancer: expression and pathophysiol ogical implications

Lung cancers express multiple factors that hold some role in the regulating networks supporting their ectopic growth. Recently, increased interest is developing in the expression and biological role of the neuropeptides and receptors of the Corticotropin Releasing Factor (CRF) system, the principle neuroendocrine mediator of the stress response, especially in the light of several R&D programs for small molecule antagonists that could present some anticancer therapeutic benefit. In the present article we review the literature suggesting that the CRF system could be involved in the regulation of lung cancer genesis and progression. Results demonstrated expression of immunoreactive CRF in a small percentage of lung cancer tissues. The presence of functional CRF receptors was also demonstrated in small cell lung carcinoma cell lines but not in the respective tissue biopsies, reducing the pathophysiological relevance of the former findings. Finally, in a mouse cachexia model, administration of a CRF2 agonist resulted in beneficial effects on muscle weight loss in mice with implanted fast-growing Lewis lung carcinoma, and reduced both the number of metastases and their mass. These results could be clinically exploited by presenting targets of new therapeutic approaches. Funding This research has been co-financed by the European Union (European social fund - ESF) and Greek national funds through the operational program “education and lifelong learning” of the National Strategic Reference Framework (NSRF) - research funding program: heracleitus II. Investing in knowledge society through the European social fund.

Whole DNA methylome profiling in mice exposed to secondhand smoke

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease.

Constitutive over expression of IL-1β, IL-6, NF-κB, and Stat3 is a potential cause of lung tumorgenesis in urethane (ethyl carbamate) induced Balb/c mice

Background:Lung cancer is a leading cause of cancer death. There has been found a substantial gap in the understanding of lung cancer genesis at the molecular level. We developed urethane (ethyl carbamate) induced lung tumor mice model to understand the mechanism and molecules involved in the cancer genesis. There might be many molecules involved, but we subsequently emphasized here the study of alternation in the expression of NF-κB, Stat3, and inflammatory cytokines interleukin-1β and interleukin-6 to hypothesize that the microenvironment created by these molecules is promoting tumor formation.Materials and Methods:7–8 week old Balb/c mice of either sex were given intraperitoneal (i.p.) injection of urethane (1g/kgbw) for eight consecutive weeks. Histopathological analysis was done to detect abnormality or invasions occurred in the lung tissues. Automated cell counter was used to count the number of inflammatory cells. The expression of NF-κB, Stat3, and IL-1β was observed at translational level by western blot, while the expression of IL-1β and IL-6 was observed at transcriptional level by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) method. Secretion of IL-1β and IL-6 in the blood was measured by enzyme-linked immunosorbent assay (ELISA) method at different time intervals.Results:Histopathological analysis showed various lung cancer stages hyperplasia, atypical adenomatous hyperplasia, and adenocarcinoma. Increased population of inflammatory cells, persistant expression of NF-κB, Stat3, pStat3, and IL-1β at translational level, while at transcriptional level constitutive enhanced expression of IL-1β and IL-6 followed by increased secretion of IL-1β and IL-6 in the blood were observed in urethane-injected mice in comparison to phosphate buffer saline (PBS) injected mice at 12, 24, and 36 weeksConclusions:Overexpression of key molecules such as NF-κB, Stat3, pStat3, IL-1β, and IL-6 might have caused chronic inflammation, leading to the progression of lung cancer.

Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor

Gene expression variation is an important mechanism underlying susceptibility to complex disease. In comparison with tobacco-related lung carcinogenesis, lung cancer in nonsmokers may involve important and etiologically distinct causal pathways. In this study, we conducted a genome-wide association study on spontaneous lung tumor incidence in inbred mice and identified a major susceptibility locus on mouse chromosome 2 (rs27328255, P=6.68 x 10(-7)). We then evaluated the correlations of polymorphisms with the transcription of positional candidate genes in normal lungs. Single-nucleotide polymorphism rs27328255 was consistently and strongly associated (P=7.42 x 10(-9)) in cis with transcript levels of Xrn2. We further showed that Xrn2 promotes proliferation and inhibits squamous differentiation in human lung epithelial cells and polymorphisms in human homolog XRN2 are associated with human lung cancer (rs2025811, P=1.90 x 10(-3), OR=1.20). We conclude that genetic variants regulating Xrn2 expression in cis are determinants of spontaneous lung tumor susceptibility in mice and have genetic equivalents in lung cancer susceptibility in human beings. Identifying Xrn2 as a major candidate for spontaneous lung cancer has important implications for the diagnosis and treatment of lung cancer as well as delineation of the mechanisms underlying the genesis of lung cancer in nonsmokers.

Wnt single transduction pathway and lung cancer

Wnt single transduction pathway plays a key role in fetal development and central nervous system formation, and regulates cell growth,migration and differentiation. It mainly consist of the classical Wnt βcatenin pathway and the non classical pathway. Recent researches reveal that the Wnt pathway is associated with cancer, and its important role in lung cancer genesis and development has been revealed gradually. Key words: Lung neoplasms ; β-catenin; Wnt protein

Polymorphisms in innate immunity genes and lung cancer risk in Xuanwei, China

The high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons (PAHs). The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and lung cancer risk in a population-based case-control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% CI: 0.16-0.55; P: 0.0001; false discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value <0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; P-interaction = 0.07) and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; P-interaction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the genesis of lung cancer caused by PAH-containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particularly noteworthy.

CYP2F1 genetic polymorphism: Identification of interethnic variations

Since human cytochrome P450 2F1 (CYP2F1) is predominantly expressed in lung tissue and is involved in the metabolism of various pneumotoxicants with potential carcinogenic effects, variations in the nucleotidic sequence of its gene may contribute to interindividual and interethnic differences in the susceptibility to lung tumorigenesis. The aim of the current study was to compare the frequency of a previously reported frameshift mutation, namely c.14_15insC, responsible for the synthesis of a severely truncated protein, between several populations of different ethnic origins. The frequencies of this polymorphism were 26.1, 51.6, 42.7 and 22.9% in French, Gabonese, Senegalese, and Tunisian population samples, respectively, thereby representing a substantial inter ethnic variation in the CYP2F1 gene. These findings provide data for further studies that investigate the potential association of CYP2F1 haplotypes with an incidence of lung cancer genesis in respect of ethnicity.

Expression and Significance of Survivin mRNA in Lung Cancer of Different Progression Stages by FISH and Tissue Microarray Technology

Objective: To investigate the expression of Survivin mRNA in lung cancer progression tissue microarray by FISH (fluorescence in situ hybridization) method and determine its role and significance in lung cancer genesis and progress. Methods: The expression of Survivin mRNA was detected by FISH method and tissue microarray technology. 89 cases of primary lung cancer, 12 cases of lymph node metastasis of lung cancer, 12 cases of precancerous lesion and 10 cases of normal lung tissue were examined. Results: 69.7% of primary lung cancer express Survivin mRNA; the positive ratio of primary lung cancer and precancerous lesion were both significantly higher than that of normal lung tissue (P<0.05); the expression of Survivin mRNA was related to the differentiation degree, lymph node metastasis and clinical stages (P<0.05). Conclusion: FISH has good sensitivity and stability. Tissue microarray technology has many advantages, such as high efficiency, high throughput, etc; it may have good prospect in pathology. Survivin mRNA was highly expressed in lung cancer and precancerous lesion; it was related to the progress and malignant behavior; it may play a promotion role in lung cancer genesis and progress and offer basis to early diagnosis, prognosis estimate and treatment.

Nicotine prevents the apoptosis induced by menadione in human lung cancer cells

Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on lung cancer and other illnesses. Nicotine is a main component in tobacco and has been implicated as a potential factor in the pathogenesis of human lung cancer. However, the mechanism of nicotine action in the development of lung cancer remains largely unknown. In the present study, we designed a nicotine-apoptosis system, by pre-treatment of nicotine making lung cancer cell A549 to be in a physiological nicotine environment, and observed that nicotine promoted cell proliferation and prevented the menadione-induced apoptosis, and exerts its role of anti-apoptosis by shift of apoptotic stage induced by menadione from late apoptotic stage to early apoptotic stage, in which NF-κB was up-regulated. Interference analysis of NF-κB in A549 cells showed that knock down of NF-κB resulted in apoptosis promotion and counteracted the protective effect of nicotine. The findings suggest that nicotine has potential effect in lung cancer genesis, especially in patients with undetectable early tumor development and development of specific NF-κB inhibitors would represent a potentially exciting new pharmacotherapy for tobacco-related lung cancer.